How do neurons age? A focused review on the aging of the microtubular cytoskeleton.

Aging is the leading risk factor for Alzheimer's disease and other neurodegenerative diseases. We now understand that a breakdown in the neuronal cytoskeleton, mainly underpinned by protein modifications leading to the destabilization of microtubules, is central to the pathogenesis of Alzheimer's disease. This is accompanied by morphological defects across the somatodendritic compartment, axon, and synapse.

Auditory temporal acuity improves with age in the male mouse auditory thalamus: A role for perineuronal nets?

The ability to perceive and interpret environmental sound accurately is conserved across many species and is fundamental for understanding communication via vocalizations. Auditory acuity and temporally controlled neuronal firing underpin this ability. Deterioration in neuronal firing precision likely contributes to poorer hearing performance, yet the role of neural processing by key nuclei in the central auditory pathways is not fully understood.

The Extracellular Environment of the CNS: Influence on Plasticity, Sprouting, and Axonal Regeneration after Spinal Cord Injury.

The extracellular environment of the central nervous system (CNS) becomes highly structured and organized as the nervous system matures. The extracellular space of the CNS along with its subdomains plays a crucial role in the function and stability of the CNS. In this review, we have focused on two components of the neuronal extracellular environment, which are important in regulating CNS plasticity including the extracellular matrix (ECM) and myelin.

Distinct phenotypes of three-repeat and four-repeat human tau in a transgenic model of tauopathy.

Tau exists as six closely related protein isoforms in the adult human brain. These are generated from alternative splicing of a single mRNA transcript and they differ in the absence or presence of two N-terminal and three or four microtubule binding domains. Typically all six isoforms have been considered functionally similar.

Microtubule stabilising peptides rescue tau phenotypes in-vivo.

The microtubule cytoskeleton is a highly dynamic, filamentous network underpinning cellular structure and function. In Alzheimer's disease, the microtubule cytoskeleton is compromised, leading to neuronal dysfunction and eventually cell death. There are currently no disease-modifying therapies to slow down or halt disease progression.

Rescue from tau-induced neuronal dysfunction produces insoluble tau oligomers.

Aggregation of highly phosphorylated tau is a hallmark of Alzheimer's disease and other tauopathies. Nevertheless, animal models demonstrate that tau-mediated dysfunction/toxicity may not require large tau aggregates but instead may be caused by soluble hyper-phosphorylated tau or by small tau oligomers. Challenging this widely held view, we use multiple techniques to show that insoluble tau oligomers form in conditions where tau-mediated dysfunction is rescued in vivo.

Soluble axoplasm enriched from injured CNS axons reveals the early modulation of the actin cytoskeleton.

Axon injury and degeneration is a common consequence of diverse neurological conditions including multiple sclerosis, traumatic brain injury and spinal cord injury. The molecular events underlying axon degeneration are poorly understood. We have developed a novel method to enrich for axoplasm from rodent optic nerve and characterised the early events in Wallerian degeneration using an unbiased proteomics screen.

Low endogenous and chemical induced heat shock protein induction in a 0N3Rtau-expressing Drosophila larval model of Alzheimer's disease.

Reduction of tau phosphorylation and aggregation by manipulation of heat shock protein (HSP) molecular chaperones has received much attention in attempts to further understand and treat tauopathies such as Alzheimer's disease. We examined whether endogenous HSPs are induced in Drosophila larvae expressing human tau (3R-tau) in motor neurons, and screened several chemical compounds that target the HSP system using medium-throughput behavioral analysis to assay their effects on tau-induced neuronal dysfunction in vivo. Tau-expressing larvae did not show a significant endogenous HSP induction response, whereas robust induction of hsp70 was detectable in a similar larval model of polyglutamine disease.

What is the pathological significance of tau oligomers?

Insoluble aggregates of the microtubule-associated protein tau characterize a number of neurodegenerative diseases collectively termed tauopathies. These aggregates comprise abnormally hyperphosphorylated and misfolded tau proteins. Research in this field has traditionally focused on understanding how hyperphosphorylated and aggregated tau mediates dysfunction and toxicity in tauopathies.

Modelling tauopathies in Drosophila: insights from the fruit fly.

Drosophila melanogaster is an experimentally tractable model organism that has been used successfully to model aspects of many human neurodegenerative diseases. Drosophila models of tauopathy have provided valuable insights into tau-mediated mechanisms of neuronal dysfunction and death. Here we review the findings from Drosophila models of tauopathy reported over the past ten years and discuss how they have furthered our understanding of the pathogenesis of tauopathies.

Expression of the MAST family of serine/threonine kinases.

The Microtubule-Associated Serine/Threonine Kinase family (MAST1-4, and MAST-like) is characterised by the presence of a serine/threonine kinase domain and a postsynaptic density protein-95/discs large/zona occludens-1 domain (PDZ). This latter domain gives the MAST family the capacity to scaffold its own kinase activity. In the present study we have profiled the mRNA for each member of the MAST family transcripts across various tissues, with particular focus on rodent brain.